DESCRIPTION: Respiratory epithelium is a tissue component whose development is regulated by vitamin A and altered by inhaled pollutants. In vitamin A-deficient condition, the epithelium undergoes the characteristic morphological changes, a phenomenon called the squamous cell metaplasia. A similar lesion can be seen in patients with a long history of heavy tobacco smoking and in animals exposed to tobacco smoke. The biochemical mechanism of the squamous cell metaplasia is not known. In this proposal, the applicant focuses on studies related to the initial proliferative phase of this lesion. The hypothesis of this proposal is that vitamin A regulates negatively the expression of TGF- alpha, and the upregulation of this gene in vitamin A-deficient airway epithelium is involved in the development of vitamin A deficiency- dependent squamous cell metaplasia in vivo. A similar hypothesis is proposed for a tobacco smoke-induced lesion in which smoke exposure enhances the TGF-alpha synthesis that is involved in tobacco smoke- induced squamous cell metaplasia. Specific aims of this proposal are: (1) to investigate the autocrine and/or paracrine nature of TGF-alpha in the regulation of cell growth of vitamin A-deficient airway epithelium by using antibodies that neutralize TGF-alpha and its receptor in both cell and organ culture systems; (2) to elucidate the mechanism of vitamin A down-regulating TGF-alpha gene expression, by testing the hypothesis that vitamin A negatively regulates the transcription of the TGF-alpha gene in primary human and monkey tracheobronchial epithelial cultures and various cell lines; (3) to elucidate the role of TGF-alpha expression in tobacco smoke-induced squamous cell metaplasia of airway epithelium by testing the effects of mainstream and sidestream smoke on the production of TGF-alpha gene product in both cell culture and transplanted tracheal graft systems, and also by using the neutralizing antibody approach; (4) to elucidate the mechanism of tobacco smoke on the regulation of TGF-alpha gene expression in airway epithelium by quantifying the TGF-alpha gene products and elucidating transcriptional or posttranscriptional mechanisms involved in the regulation of this gene expression by tobacco smoke.